ACC: Take-Home on Two Trials Not Strictly by the Book

Action Points

Note that in the STICH trial comparing medical therapy alone with medical therapy plus CABG there was no significant difference with respect to the primary endpoint though results on secondary endpoints favored CABG.

Note that in the PRECOMBAT trial, PCI with sirolimus-eluting stents was shown to be noninferior to CABG with respect to major adverse cardiac or cerebrovascular events; however, the noninferiority margin was wide, leaving it unclear as to the clinical relevance of the finding.

Note that the panel discussion following the presentation of STICH data interpreted the results as basically in favor of CABG.

Similarly, note that the discussion suggested that surgeons are more likely to see the results favoring CABG because of divergence in the curves "especially in those with left main and complicated, two- or three-vessel disease," despite lack of statistical difference.

NEW ORLEANS -- Two trials reported here showed no difference between treatments in left main disease and ischemic heart failure, but the practical upshot of those trials may not be the one suggested by the statistics, according to leading cardiologists at the American College of Cardiology meeting here.

The STICH trial was negative for its primary endpoint, showing no all-cause mortality benefit for coronary artery bypass grafting (CABG) over medical therapy alone in patients with coronary artery disease and low ejection fraction, yet some declared it a win for surgery.

Likewise with the PRECOMBAT trial, which found stenting noninferior to CABG for major adverse cardiac and cerebrovascular events among patients with left main coronary artery disease. Some experts in the field took away a message of divergence in outcomes.

"People are seeing what they want to see," Gregg W. Stone, MD, of New York-Presbyterian Hospital in New York City, told MedPage Today. He moderated the late-breaking clinical trial session at which both trials were presented.

Even STICHes

The STICH trial's primary endpoint was unadjusted rates of death from any cause, which showed an absolute risk reduction of 5% with CABG in ischemic heart failure compared with optimal medical therapy but without a significant difference (41% versus 36%, P=0.12).

However, the adjusted intent-to-treat analysis did significantly favor surgery at a hazard ratio of 0.82 (P=0.039).

Lead author Eric J. Velazquez, MD, of the Duke Clinical Research Institute in Durham, N.C., cautioned that this analysis was prespecified but provisional and concluded that treatment decisions should be individualized.

Stone emphasized that the trial was "technically" negative and "difficult to declare as strongly positive."

However, the ensuing panel discussion at the late-breaking trials session turned the other way.

Steven F. Bolling, MD, a cardiac surgeon at the University of Michigan in Ann Arbor, argued that statistical arguments don't hold up against clinical benefits.

He pointed to the as-treated analysis, which showed a significant 30% benefit for the primary endpoint of all-cause mortality with CABG compared with medical therapy alone (P<0.001), and the per-protocol analysis excluding crossovers, which also showed a significant benefit to CABG (HR 0.76, P=0.005).

"The biologic effect that our patients feel is really what treatment they received, and under that analysis of course as a surgeon you must conclude that patients with left ventricular dysfunction should receive coronary bypass," he concluded at the session.

"For the clinician, we now have a trial that's been very positive, STICH," he said in the panel discussion.

The significant secondary endpoint benefits with CABG for reduction in cardiovascular death and in combined all-cause mortality or cardiovascular hospitalization appeared persuasive as well for Velasquez.

"The take-home message for me is that the STICH trial supports bypass surgery on top of best medical therapy to reduce cardiovascular morbidity and mortality," Velasquez concluded at a press conference afterward.

"Many patients who are now treated for heart failure without ever being assessed for the potential of having angiographic coronary disease should now be evaluated for that," he said.

A PRECOMBAT Sortie

The PRECOMBAT trial was aimed at noninferiority, and achieved it for the comparison of sirolimus-eluting Cypher stents and CABG for the composite of all-cause mortality, myocardial infarction, stroke, and target-vessel revascularization at both one and two years of follow-up (P=0.01 for noninferiority and P=0.12 for difference, respectively).

But "the concept of a noninferiority trial is really a statistics concept and not really a biologic concept," Bolling argued in the panel discussion on this trial.

Surgeons are more likely to see the results favoring CABG due to divergence in the curves "especially in those with left main and complicated, two- or three-vessel disease," despite lack of statistical difference, he suggested.

"Had they continued the trial another six months or a year, would it become statistically significant?" Bolling posited.

Study discussant James B. McClurken, MD, a cardiothoracic surgeon at Temple University in Philadelphia, noted that longer-term follow-up will be key, possibly eight or 10 or even 20 years down the line to see if the divergence becomes significant.

PRECOMBAT followed on the heels of the SYNTAX trial comparing stents to CABG in a typically more complex group of patients that wasn't limited to left main disease. SYNTAX gave surgery the overall advantage in major cardiac and cerebrovascular adverse events but with some indications of advantage for stents in lower risk left main disease.

"We don't know exactly which groups and which circumstances," but stents looked very good in low complexity patients and there appears to be room for individualization for intermediate patients, he said at the session.

"I think we are at the point where we can discuss the option of PCI with a patient with unprotected left main disease," he added. "I think we also have to tell patients we have to wait, there's more data coming."

The STICH trial was supported by grants from the National Heart, Lung and Blood Institute and by Abbott Laboratories.

PRECOMBAT was supported by the Cardiovascular Research Foundation, Cordis, Johnson & Johnson, and a grant from the Health 21 R&D Project through the Korean Ministry of Health and Welfare.

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